Prior work from our Emphysema/COPD Research Center (ECRC), in collaboration with colleagues at the University of British Columbia, Vancouver, has provided strong evidence that adaptive immune abnormalities play a critical role in the pathogenesis of peripheral airway remodeling in Chronic Obstructive Pulmonary Disease. We will outline our evidence from both lung tissue explants and peripheral blood markers that supports this hypothesis. We further hypothesize that modulation of these immune responses with specific biologic agents could ablate, or ameliorate these pathogenic mechanisms, and alter the natural history of COPD. This proposal outlines a prototype aerosol intervention protocol based upon the long-term experience at the University of Pittsburgh with the use of aerosol cyclosporine (aCsA) for the prevention of bronchiolar inflammation in the lung transplantation population. This project will outline sequential Phase I and Phase I/I I trials to explore the short (28 days) and intermediate term (6 month) safety of aCsA immunotherapy applied to a population of patients with moderately severe (Gold III) COPD. A Phase I initial dose escalation-deescalation protocol (DEP) will examine short-term safety issues with attention to airway reactivity and infection risk. The observations learned from the DEP, will be incorporated into the design and execution of a randomized, parallel-design, moderate duration Phase I/I I exploratory trial. Our therapeutic goal in both the DEP and AIC will be to define the minimum tolerated aCsA dose associated with biologic efficacy, using peripheral blood marker bioassays. The data and human specimens from this intervention trial will be used collaboratively with Projects 1-3 of this proposal to gain insight into the pathogenesis of moderately advanced COPD under the influence of immunoregulatory control. We believe aCsA provides an immediately available, innovative, approach to potentially treat the adaptive immune response documented in COPD patients. The clinical investigation protocol outlined in this proposal will fulfill the stated application goal to identify, high-risk/high-gain tests of novel therapeutic approaches, both in animal models and as Phase l/ll clinical trials.